4-Hydroxyphenylpyruvate Dioxygenase-Like Protein Promotes Pancreatic Cancer Cell Progression and Is Associated With Glutamine-Mediated Redox Balance

Xianglai Ye; Xiujuan Wei; Jing Liao; Peipei Chen; Xueyun Li; Yulong Chen; Yue Yang; Qiongya Zhao; Hongwei Sun; Liming Pan; Guorong Chen; Xujun He; Jianxin Lyu; Hezhi Fang

doi:10.3389/fonc.2020.617190

4-Hydroxyphenylpyruvate Dioxygenase-Like Protein Promotes Pancreatic Cancer Cell Progression and Is Associated With Glutamine-Mediated Redox Balance

Front Oncol. 2021 Jan 18:10:617190. doi: 10.3389/fonc.2020.617190. eCollection 2020.

Authors

Xianglai Ye^{1

2

3}, Xiujuan Wei^{1

2

3}, Jing Liao^{1

2

3}, Peipei Chen^{1

2

3}, Xueyun Li^{1

2

3}, Yulong Chen^{1

2

3}, Yue Yang^{1

2

3}, Qiongya Zhao⁴, Hongwei Sun⁵, Liming Pan⁶, Guorong Chen⁷, Xujun He⁸, Jianxin Lyu^{1

2

3

4

8}, Hezhi Fang^{1

2

3}

Affiliations

¹ Key Laboratory of Laboratory Medicine, Ministry of Education, Wenzhou Medical University, Wenzhou, China.
² Zhejiang Provincial Key Laboratory of Medical Genetics, Department of Cell Biology and Medical Genetics, Wenzhou Medical University, Wenzhou, China.
³ College of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, China.
⁴ College of Laboratory Medicine, Hangzhou Medical College, Hangzhou, China.
⁵ Department of Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
⁶ Department of Pathology, The People's Hospital of Yuhuan, The Yuhuan Branch of the First Affiliated Hospital of Wenzhou Medical University, Taizhou, China.
⁷ Department of Pathology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
⁸ Department of Laboratory Medicine, Zhejiang Provincial People's Hospital, Affiliated People's Hospital of Hangzhou Medical College, Hangzhou, China.

Abstract

Tumor cells develop a series of metabolic reprogramming mechanisms to meet the metabolic needs for tumor progression. As metabolic hubs in cells, mitochondria play a significant role in this process, including energy production, biosynthesis, and redox hemostasis. In this study, we show that 4-hydroxyphenylpyruvate dioxygenase-like protein (HPDL), a previously uncharacterized protein, is positively associated with the development of pancreatic ductal adenocarcinoma (PDAC) and disease prognosis. We found that overexpression of HPDL in PDAC cells promotes tumorigenesis in vitro, whereas knockdown of HPDL inhibits cell proliferation and colony formation. Mechanistically, we found that HPDL is a mitochondrial intermembrane space localized protein that positively regulates mitochondrial bioenergetic processes and adenosine triphosphate (ATP) generation in a glutamine dependent manner. Our results further reveal that HPDL protects cells from oxidative stress by reprogramming the metabolic profile of PDAC cells toward glutamine metabolism. In short, we conclude that HPDL promotes PDAC likely through its effects on glutamine metabolism and redox balance.

Keywords: glutamine; metabolic reprogramming; mitochondria; pancreatic ductal adenocarcinoma; redox balance.